Virtually nothing is known about the microphysiology of synaptic transmission in the mammalian brain, owing to the lack of a suitable experimental preparation. My collegues and I have developed the in vitro hippocampal slice preparation to the point of demonstrating that quantal levels studies are now feasible in hippocampal neurons. In particular, we have been able to resolve, for the first time in mammalian brain, spontaneous miniature synaptic potentials. Furthermore, we have demonstrated that the electrotonic structure of the postsynaptic cell and the location of the synapse of interest, relative to the somal recording site, are almist ideal. In addition, we have been able to voltage-clamp both evoked synaptic currents and spontaneous miniature synaptic currents. The ultimate objective of this project is, first, to develop quantitatively the fundamental facts and laws concerning the quantal nature of spontaneous and evoked transmitter release in certain visually identifiable classes of hippocampal neurons. Second, this background information will then be used as part of an effort to determine the mechanisms responsible for the well-known phenomenon of long-term synaptic potentiation (LTP) in this system. The particular synapses selected for study is the granule cell mossy fibre to CA3 pyramidal cell synapse. The following specific aims will be pursued in the order listed using current- and voltage-clamp techniques, the results of which will be interpreted with the aid of computer simulations. (1) Several methods will be used to evaluate the approximate electrotonic structure of the postsynaptic cell for the purpose of understanding the effect of the passive cable properties on synaptic events recorded in he soma. (2) The statistical features of spontaneous and evoked quantal release will be analyzed to determine whether the classical laws of quantal release apply to these synapses. (3) The kinetics of LTP will be examined under various ionic and stimulation conditions to compare the results obtained using the traditional extracellular recording methods with those obtained intracellularly under current- and voltage-clamp. (4) Five hypotheses for LTP will be tested.